From a molecular standpoint, aging can be considered as a broad- based regulatory dysfunction. One of the most important classes of regulatory factors is the hormone receptor. Programmed reproductive senescence is nature's precautionary design to prevent vertical transmission of the genetic material damaged through chronologically accumulated environmental insults. This provides an additional impetus for age-dependent regulation of the receptors for reproductive hormones. Studies in our laboratory have clearly shown that the androgen sensitivity of the rat liver decreases markedly during senescence. This conclusion was initially drawn from the observed loss of androgen-dependent synthesis of alpha2u globulin during aging (1). Subsequent findings on age-dependent increased hepatic synthesis of SMP-2 (an androgen-repressible protein) proved that this is indeed a regulatory defect, and is not due to age-associated degenerative changes (2). More recently, we have obtained evidence for the loss of expression of the androgen receptor gene as the basis for hepatic androgen insensitivity during senescence. The above considerations, together with the fact that normal hepatocytes in intact animals do not undergo mitosis more than once during adult life, make the study of hepatic androgen insensitivity during aging an ideal model to explore the molecular basis for age- dependent regulatory dysfunctions. It should also be emphasized that dysfunctions of the liver in the elderly have important pharmacokinetic implications, as the systemic half-lives of many therapeutic agents are determined by the hepatic metabolism via cytochrome P-450 enzymes. Sexual dimorphism of these drug- metabolizing enzymes is a well-documented phenomenon (3,4). Recent developments in molecular biological and transgenic technologies have made it possible to ask several fundamental questions regarding the regulation of androgen receptor expression and function during aging. As elegantly set forth by the renowned hepatologist Hans Popper, "...the effect of age on the liver and the liver on aging is full of promise if available methodologies are rigorously applied" (5). Project 6 has been developed to take advantage of the current and emerging technologies complemented by our extensive experience in the area of hepatic gene expression during aging, and the general theme of the overall program.